Disease or injury of the brain is a major cause of death and morbidity, and often produces long-term disability with unusually high accompanying social and medical costs. EP2 receptor activation has been shown to be neuroprotective in several animal models of acute cerebral ischemia. We have recently created the first allosteric potentiators of the EP2 receptor for PGE2 and have shown they are neuroprotective in vitro. Patients experiencing a subarachnoid hemorrhage are at substantial risk of experiencing a stroke-like ischemic event 4-14 days after their surgery to coil or clip their aneurysm. Neuroprotective agents can be administered to this population prior to the ischemic event under intensive care monitoring. The work proposed here is aimed at identifying a context-dependent allosteric potentiator of the EP2 receptor that is suitable for prophylactic use in the clinical setting for the treatment of SAM patients. Our prototype compound has good plasma half-life and brain penetration, but solubility and/or potency must be improved to be practical for systemic administration in vivo. The goal of the proposed research is to develop a small molecule allosteric potentiator of human EP2 receptors, progress it through preclinical safety testing to IND submission, and then to carry out a phase I clinical trial for treatment of cerebral injury following subarachnoid hemorrhage. We have developed a suite of cell-based EP2 receptor assays that have the requisite throughput and disease relevance, and have identified several promising lead molecules that will be further refined in collaboration with the Blueprint for Neuroscience Research team to improve potency, ADMET and pharmaceutical properties to deliver a compound suitable for filing an IND. We will work with the Blueprint team to establish the requisite preclinical safety package and dosing interval for use in SAH patients to support an IND. An IND will be filed within the project period and a phase I clinical trial initiated shortly thereafter. PUBLIC HEALTH RELEVANCE: Disease or injury of the brain is a major cause of death and morbidity, and often produces long-term disability with unusually high accompanying social and medical costs. We intend to create novel drugs that target inflammation pathways to minimize the cognitive deficits that often accompany brain injury. We specifically focus on injury that is associated with subarachnoid hemorrhage.